Despite warnings of the teratogenic effects of tobacco use during pregnancy, estimates show that between 15 and 30% of all pregnant women in the US smoke. This leads to an alarming 700,000 children each year that are exposed to tobacco constituents in utero. Among the many reported negative outcomes of in utero nicotine exposure is a 3-5 fold elevated risk for the development of nicotine dependence. Rodent studies have supported the findings that developmental nicotine exposure increases negative outcomes, including increased risk for nicotine consumption. The mechanism(s) underlying the increased rate of smoking among in utero exposed children have not been elucidated. However, the women most prone to continue smoking during pregnancy are those at elevated genetic risk for nicotine dependence. Therefore, the elevated risk of nicotine dependence in their offspring could be due to inherited risk factors, in utero exposure, or both. Our laboratory recently has developed a mouse model that carries a human genetic variation in a gene named CHRNA5. Importantly for this application, women who have the risk version of this gene are less likely to stop smoking during pregnancy. Preliminary data from the mouse model indicate that mice with the risk version of the gene and exposed to nicotine in utero will consume the highest levels of nicotine suggesting an additive effect of genetic risk and environment. Strikingly and unexpectedly, however, offspring with the non-risk variant that were developmentally exposed to nicotine exhibited a dramatic reduction in nicotine intake during adolescence as compared to their genotype matched controls. This novel finding indicates that the direction of effect of developmental nicotine exposure on subsequent risk for nicotine intake is genotype dependent and challenges the notion that prenatal nicotine exposure alone is a risk factor for the development of nicotine dependence. To better appreciate how genotype and developmental nicotine exposure interact to dramatically alter outcomes, this exploratory project proposes two specific aims. Because alterations in nicotine consumption can be through altered reward or/and aversion to nicotine, we will determine the impact of nicotine exposure and genotype on these motivated behaviors. We also will assess whether the interaction between genotype and nicotine exposure to alter nicotine intake is due to the genotype of the offspring. In addition, we will assess the effect of genotype and prenatal nicotine exposure on the functional properties and structure of layer VI prefrontal cortical pyramidal cells that project to select brain areas relevant to reward and aversion. Understanding how genotype modifies the effect of developmental nicotine exposure on nicotine reward and brain circuits that modulate these behaviors will provide unique insight into the behavioral and neurophysiological mechanisms through which prenatal nicotine exposure alters risk for nicotine dependence.